Understanding the Risk of Antifungal Resistance

Invasive fungal infections, though less frequently encountered than bacterial and viral infections, can be devastating, particularly in immunocompromised patients. The rise of antifungal resistant pathogens, like Candida auris and Aspergillus fumigatus, has only heightened this concern. But how common is antifungal resistance? Who is at risk? What pathogens are of particular concern, and how significant is the overall threat?

ASM's "Meet the Microbiologist" podcast breaks down the topic of antifungal resistance with Gary Procop, Ph.D., CEO of the American Board of Pathology and professor of pathology at the Cleveland Clinic, and Shawn Lockhart, Ph.D., Senior Clinical Laboratory Advisor in the Mycotic Diseases Branch at the U.S. Centers for Disease Control and Prevention (CDC).

How Common Is Antifungal Resistance?

Methods of horizontal gene transfer conferring antimicrobial resistance in bacteria.
Source: ASM. According to Procop, antifungal resistance is very different from antibacterial resistance. “I mean, these really are apples and oranges,” Procop explained. The reason? Fungi are eukaryotic organisms that possess relatively stable genomes compared to their bacterial counterparts. When it comes to the acquisition of antimicrobial resistance (AMR), that stability makes a difference.

Prokaryotic organisms are considered to be highly promiscuous in the exchange of genetic material—taking advantage of methods of horizontal gene transfer. Although some fungi can, and do, exchange genetic material, the relative stability that eukaryotes possess, compared to prokaryotes, makes the acquisition and development of antifungal resistance rarer than that of antibiotic resistance.

“We did a study years ago, looking at Cryptococcus, and CDC did a similar study. We both had the same finding,” said Procop.

In this study, scientists looked at 3 different cryptococcal isolates from 3 different areas of the globe—the U.S., Thailand and Malawi. The sites differed in antifungal use in the following manner:

1. One site required a prescription for patients to acquire antifungal drugs.
    
2. One site distributed antifungals over the counter.
    
3. One site fell somewhere in the middle—antifungals were not as readily available as over the counter, but also not overly difficult to obtain.

Importantly, despite these differences in antifungal stewardship practices, there was no significant difference in Cryptococcus resistance to a slew of antifungals (amphotericin B, fluconazole, itraconazole, 5-flucytosine and ketoconazole) among isolates collected from the 3 locations.

"We did that same study when ESBL, extended spectrum beta lactamases, were just coming out in gram-negatives," Procop said. This time, researchers evaluated antimicrobial susceptibility of gram-positive cocci and gram-negative bacillus in bloodstream isolates collected from 5 hospitals in Cairo, Egypt where, at the time (1999-2000), antibiotics were available over the counter. The team found significant differences in susceptibility profiles compared to samples collected in locations where a prescription was required for antibiotic use. "Of course, where there were more antibiotics, there was more resistance," Procop summarized.

He explained that this knowledge logically shifts his focus in the clinical laboratory from antifungal susceptibility testing to fungal identification. "We will often say, 'If you can get to the identification, you've got some good information about the likelihood of responses to certain drugs.' In my mind, anyway, identification becomes priority to antifungal susceptibility testing."

Still, he acknowledged that this doesn't hold true for all organisms. The profiles of some fungi (i.e., Fusarium), are much harder to predict and that’s where the CLSI Antifungal Susceptibility Subcommittee comes into play. CLSI repeatedly tests rare fungi to determine accurate breakpoint information if/when sufficient clinical trial data does not exist. Essentially, the group identifies the normal distribution of rare fungi, with respect to minimal inhibitory concentrations (MICs), against different antifungals and publishes the resulting epidemiologic cut off values (ECVs).

"From that, you can kind of see how these fungi are probably going to act," Procop explained, adding that the CLSI has also developed lists of fungal groups that possess intrinsic resistance. "For example, you know that Canada krusei is intrinsically resistant to fluconazole. So, I think knowing the intrinsic resistance profile is very important. Then, if you have an identification, that can be used to help guide therapy."
 

Who Is at Risk of Contracting Invasive Fungal Infections?

Both Procop and Lockhart emphasized that, although invasive fungal infections are rarer than bacterial and/or viral infections, and the development of antifungal resistance is less frequent, fungal infections can be devastating, especially in vulnerable populations (e.g., people with weakened immune systems or who are immunocompromised, those who have experienced stem cell or organ transplant and those who have cancer or are undergoing chemotherapy). It is a fact that provides a new metric for evaluating the severity of the threat of antifungal resistance.

"Normally, healthy patients don't get fungal infections—at least fungal infections that are beyond the superficial. But that makes them especially disturbing, because the people who are susceptible to fungal infections are the people who already have serious underlying conditions, and that makes them less likely to survive a fungal infection," explained Lockhart.

This vulnerability may be compounded by delays in diagnoses, due to the simple fact that fungi tend to be considered after viral and bacterial candidates have been ruled out in the differential diagnosis. If any type of drug resistance is added to the equation, the unrestrained pathogen wreaks havoc.

"At that point, a lot of times it can be too late," said Lockhart, whose clinical microbiology fellowship included a distinct emphasis on antifungal resistance.

What Fungi Are of Particular Concern for Antifungal Resistance?

Lockhart pointed out that, relatively speaking, acquired antifungal resistance is rare, even in Candidas (~ 7%). Yet, C. auris, Candida parapsilosis and A. fumigatus are 3 fungal pathogens that have "broken the mold" on antifungal resistance.
 

Candida auris

"What we're seeing now is this rise in a brand-new bug called C. auris that very easily acquires resistance. We've even seen pan-resistance in C. auris, which is something we've never seen or experienced before. And yet, here it is, all of a sudden. It's literally spreading across the world,” Lockhart said, adding that new states where C. auris is detected in the U.S. are being reported each year.

C. auris carries a high mortality rate, killing more than 1 in 3 people with infections, and has demonstrated pan-drug resistance to at least 4 classes of antifungal agents. According to the CDC, about 90% of U.S. isolates are resistant to fluconazole, 30% are resistant to amphotericin B and >5% are resistant to echinocandins.

C. auris is typically found in hospital or health care settings and is capable of causing hospital acquired infections in immunocompromised people. When asked about the course of infection, Lockhart explained that C. auris follows an outside-in phenomenon. “Most of these patients have multiple central lines—they often have feeding tubes and they're often on ventilators. You have all these devices that go from the outside of the patient to the inside of the patient that are just providing portals for C. auris to get to the inside.” According to Lockhart, 5-10% of patients who become colonized with C. auris go on to develop bloodstream infections, which can be life-threatening.

Candida parapsilosis

Resistant C. parapsilosis is another Candida species that is raising alarm bells. "It tends to be single clones that rise in a geographic area and spread hospital-to-hospital. We don't know how or why yet, but that's something that we have an interest in," Lockhart explained.

C. parapsilosis typically functions as a skin and gut commensal organism, but once again, in hospital settings and immunocompromised patients it may follow an outside-in course of infection that leads to bloodstream and/or internal organ infection. Still, according to the Cleveland Clinic, less than 0.01% of people get invasive candidiasis of any type each year.

Aspergillus fumigatus

Importantly, not all antifungal resistance is experienced (or spread) in the hospital. "The other bit of acquired resistance that we've never seen before is azole-resistant A. fumigatus, and that's caused by the use of azole antifungals or fungicides that are sprayed on agricultural fields," Lockhart stated.

Today, the U.S. alone is using 4 times as much fungicide as it was using just 5 years ago, and as these fungicides continue to be sprayed, the repeated exposure ultimately selects for resistant A. fumigatus clones over susceptible ones. Furthermore, according to Lockhart, A. fumigatus is everywhere, and there doesn’t appear to be a fitness cost to the organism carrying azole resistance.

"We catch Aspergillus from the environment," he explained. "The spores are literally all over us. You can stomp on your carpet in front of you right now, and I guarantee you will be spreading A. fumigatus spores—they're just ubiquitous. And so, we're going to see more and more patients that show up at the hospital with an already resistant case of pulmonary aspergillosis."

Should A. fumigatus spores be inhaled, the innate immune system of healthy individuals is usually effective at warding off infection. However, aspergillosis may become localized or invasive in more vulnerable populations. Similar to the examples of candidiasis mentioned above, symptoms (coughing up blood, fever and chills, headaches, chest pain, shortness of breath, among others) largely depend on the organs that are infected, and the mortality rate of proven invasive pulmonary aspergillosis in immunocompromised patients is very high (between 40-90%).
 

The Takeaway: Antifungal Resistance Is a Growing Threat That Must Be Managed

While antifungal resistant infections remain significantly overshadowed by antibacterial infections in terms of frequency, the severity of disease experienced by immunocompromised patients with invasive fungal infections presents a confounding factor when evaluating the threat of antifungal resistance. Early diagnosis can help, but use of antifungals in the environment and in health care settings must be properly managed in order to protect vulnerable populations and retain the strong arsenal of antifungal classes that exist.

Read More About Combating Antifungal Resistance

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In This Issue:

• Lessons From a Decade of Antimicrobial Resistance Policy
• Growing Resistance: How Plant Agriculture Contributes to AMR
• Understanding the Risks of Antifungal Resistance
• Experts in East Africa Propose Equitable AMR Interventions
• Wastewater As a Key Driver of AMR
• Exploring a One Health Approach to AMR in Pakistan
• Federally Qualified Health Centers Lead AMR Stewardship
• Updating Breakpoints in Antimicrobial Susceptibility Testing
• Hunting for Antibiotics in Unusual and Unculturable Microbes
• What's Hot in the Microbial Sciences